Project 4 is focused on testing the safety of novel inhaled mucolytic compounds in persons with asthma (specific aim 1), testing these in an allergen challenge model of acute exacerbation in mild mite allergic asthmatics (specific aim 2), and examining the effect of such compounds on mucociliary clearance (MCC) and lung function in moderate asthmatics on stable controller therapy over a 2-week period (specific aim 3). Studies from our group indicate that S-S bonds are a key element in increased viscosity of mucus in asthma and have catalyzed the study of thiol based mucolytics for asthma in this tPPG. The best candidate for this intervention is P2176, a di-thiol mucolytic which has robust ability to degrade mucins in sputum samples from asthmatics in vitro, has been well tolerated in animals in pre-clinical studies, and is currently in Phase I studies of healthy volunteers. Safety studies of P2176 in asthmatics will be the major focus in years 1-2. In years 2-5, we will begin to screen mite-allergic asthmatics for late phase responsiveness to mite allergen, and begin to pursue aims 2 and 3.
Specific Aim 2 will examine the effect of P2176 on an allergen-induced late phase response, which we have shown is associated with increased mucus secretion and decreased MCC. Success with SA2 would suggest a role for mucolytics in acute exacerbation of asthma.
Specific Aim 3 will examine the effect of 2 weeks daily treatment on MCC in volunteers with moderate asthma. If successful, this study would indicate the P2176 has a role in maintenance therapy for asthma in persons with long term mucus-derived airway obstruction.
The proposed research will investigate whether novel inhaled mucolytics can improve mucus transport and reduce airways obstruction in asthma. If successful, this research may significantly accelerate the development of therapies that improve the health of patients with airways diseases, including CF, chronic bronchitis, and asthma.
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